The immediate early gene c-fos couples neural activity to gene expression and has been widely used as a marker to identify stimulus-specific neural ensembles. Here we propose to create and characterize transgenic mice that use the c-fos promoter to drive expression of the light-activated cation channel, channelrhodopsin (ChR), coupled to the yellow-fluorescent protein YFP. This proposal presents a fusion of cutting-edge technologies (direct visualization of gene expression and use of light-activated ion channels for circuit reactivation) that facilitate investigation of novel questions in systems neuroscience. Fos-ChR transgenic mice will allow us to 1) mark the identity of activated cells and 2) subsequently drive activity in these neurons to test the role of specific neurons in perception and behavior. Controlled reactivation of neuronal subsets will answer important questions about how specific neuronal subsets encode perception and behavior, and may facilitate active retraining of maladaptive neural circuits that have been altered by drug exposure or disease. PUBLIC HEALTH RELEVANCE: The mammalian brain contains millions to trillions of neurons that drive a wide array of complex behaviors. Understanding how specific neuronal ensembles are engaged by and encode perception and behavior requires identification and analysis of these neural subsets. Expression of the immediate-early gene c-fos can "mark" populations of task- or stimulus-specific neurons, providing a functional criterion to define neural subpopulations. Using fos gene promoter sequences to drive expression of the light-activated cation channel, channelrhodopsin, (ChR) we will create and characterize fos-ChR transgenic mice. These animals will enable us to identify and then reactivate functionally-defined neural ensembles to understand how the controlled reactivation of small subsets of neurons can drive perception and behavior. In addition, neural reactivation may allow retraining of specific circuits to eliminate maladaptive behaviors in addiction or psychiatric disorders.